DESCRIPTION (from Applicant's abstract) Neurofibrillary tangles are a major pathological hallmark of Alzheimer's disease (AD). These tangles contain abnormal paired helical filaments (PHF), whose primary component is tau. Tau is a neuronal microtubule associated protein that is essential for the development and maintenance of axons. Tau in tangles is abnormally phosphorylated on serines and threonines but the significance of these phosphorylations and the pathways leading to tangle formation remain unknown. The applicant now finds that tau associates with src family non-receptor tyrosine kinases, including fyn, and that tau is tyrosine phosphorylated in human neuroblastoma cells. Moreover, they find that anti-phosphotyrosine antibodies react with PHF-tau from AD brain and that anti- phosphotyrosine staining co-localizes with the anti-PHF staining of neurofibrillary lesions in AD brain. Consistent with these results, other studies find that fyn is up-regulated in AD and that an increase in tyrosine phosphorylation follows exposure of neuronal cells to A-beta peptide. Based on her findings, other studies, and the key role played by tyrosine phosphorylation in signal transduction during growth and development, the applicant hypothesizes that tyrosine phosphorylation of tau plays a critical role in neurofibrillary tangle formation in Alzheimer's disease. Here it is proposed to determine the impact of tyrosine phosphorylation on the function of tau and to assess the role of tyrosine phosphorylation of tau in tangle formation. In Aim I, they will identify the tyrosine in tau that is phosphorylated and determine how tyrosine phosphorylation affects the function of tau. In Aim II, they will further characterize the tyrosine phosphorylation of tau in AD brain and in their lamprey model for human tau filament assembly in situ. In Aim III, they will determine the expression of tyrosine phosphorylation of tau during neuronal differentiation, brain development, aging and disease. These studies will help determine the role of tyrosine phosphorylation of tau in PHF assembly and may aid in the development of mouse models of AD. Moreover, since the A-beta peptide increases tyrosine phosphorylation in neuronal cells, tyrosine phosphorylation may be the link between amyloid plaque formation and neurofibrillary tangles. Insights into the tyrosine phosphorylation of tau may provide an important step forward in elucidating the pathways leading to neurofibrillary tangle formation in AD.